HDAC3 inhibition upregulates PD-L1 expression in B-cell lymphomas and augments the efficacy of anti-PD-L1 therapy
Open accessAbstract
Abstract Programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers, including B-cell lymphoma. The clinical response to PD-1/PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Here, we report that histone deacetylase 3 (HDAC3) is a crucial repressor of PD-L1 transcription in B-cell lymphoma. Pan-HDACs or selective HDAC3 inhibitors could rapidly increase histone acetylation and recruitment of bromodomain protein BRD4 at the promoter region of PD-L1 gene, leading to activation of its transcription. Mechanically, HDAC3 and its putative associated corepressor SMRT were recruited to the PD-L1 promoter by the transcriptional repressor BCL6. In addition, HDAC3 inhibition reduced DNA methyltransferase 1 protein levels to indirectly activate PD-L1 transcription. Finally, HDAC3 inhibition increased PD-L1 expression on dendritic cells in the tumor microenvironment. Combining selective HDAC3 inhibitor with anti–PD-L1 immunotherapy enhanced tumor regression in syngeneic murine lymphoma model. Our findings identify HDAC3 as an important epigenetic regulator of PD-L1 expression and implicate combination of HDAC3 inhibition with PD-1/PD-L1 blockade in the treatment of B-cell lymphomas.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In B-cell lymphomas, HDAC3 is recruited by BCL6 as part of a complex with NCOR1/NCOR2 to the PD-L1 promoter.
“In B-cell lymphomas, HDAC3 is recruited by BCL6 as part of a complex with NCOR1/NCOR2 to the PD -L1 promoter.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Deng et al., 2019
In the presence of PD-L1, RGFP966 acted synergistically with anti-PD-L1 therapy to suppress tumor growth.
“In the presence of PD-L1, RGFP966 acted synergistically with anti PD-L1 therapy to suppress tumor growth (Deng et al., 2019).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Deng et al., 2019
Silencing of HDAC3 promotes PD-L1 expression.
“Consistent with this, silencing of HDAC3 promotes PD-L1 expression.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Deng et al., 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609 · cited 1× · see citing works
“In cancer patients, the clinical response to PD-L1/PD-1 immunotherapy correlates with tumor and host PD-L1 expression, along with other predictive biomarkers such as tumor-infiltrating CD8þ T cells and mutation burden (9, 10).”
BackgroundPredictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Herbst, R. S., Soria, J.-C., Kowanetz, M., Fine, G. D., Hamid, O., Gordon, M. S., Sosman, J. A., McDermott, D. F., Powderly, J. D., Gettinger, S. N., et al. (2014) · Nature · doi:10.1038/nature14011 · Cited by 5,231 · see citing works
Zou, W., Wolchok, J. D., & Chen, L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7118 · Cited by 2,382 · see citing works
Regulation and Function of the PD-L1 Checkpoint
Sun, C., Mezzadra, R., & Schumacher, T. N. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.014 · Cited by 2,187 · see citing works
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Francisco, L. M., Salinas, V. H., Brown, K. E., Vanguri, V. K., Freeman, G. J., Kuchroo, V. K., & Sharpe, A. H. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090847 · Cited by 2,072 · see citing works
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.011 · Cited by 2,022 · see citing works
Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression
Garcia-Diaz, A., Shin, D. S., Moreno, B. H., Saco, J., Escuin-Ordinas, H., Rodriguez, G. A., Zaretsky, J. M., Sun, L., Hugo, W., Wang, X., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.031 · Cited by 1,942 · see citing works
Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future
Chen, L., & Han, X. N. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80011 · Cited by 1,433 · see citing works
New and emerging HDAC inhibitors for cancer treatment
West, A. C., & Johnstone, R. W. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69738 · Cited by 1,404 · see citing works
MYC regulates the antitumor immune response through CD47 and PD-L1
Casey, S. C., Tong, L., Li, Y., Do, R., Walz, S., Fitzgerald, K. N., Gouw, A. M., Baylot, V., Gütgemann, I., Eilers, M., et al. (2016) · Science · doi:10.1126/science.aac9935 · Cited by 1,403 · see citing works
Green, M. R., Monti, S., Rodig, S. J., Juszczyński, P., Currie, T., O'Donnell, E., Chapuy, B., Takeyama, K., Neuberg, D. S., Golub, T. R., et al. (2010) · Blood · doi:10.1182/blood-2010-05-282780 · Cited by 1,307 · see citing works
Targeting bromodomains: epigenetic readers of lysine acetylation
Filippakopoulos, P., & Knapp, S. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4286 · Cited by 1,274 · see citing works
Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity
Hirano, F., Kaneko, K., Tamura, H., Dong, H., Wang, S., Ichikawa, M., Rietz, C., Flies, D. B., Lau, J. S., Zhu, G., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.1089.65.3 · Cited by 1,018 · see citing works
Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., et al. (2018) · Nature · doi:10.1038/nature25015 · Cited by 1,013 · see citing works
Kelly, W. K., O’Connor, O. A., Krug, L. M., Chiao, J. H., Heaney, M. L., Curley, T., MacGregor‐Cortelli, B., Tong, W. P., Secrist, J. P., Schwartz, L. B., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.14.167 · Cited by 906 · see citing works
Juneja, V. R., McGuire, K. A., Manguso, R. T., LaFleur, M. W., Collins, N. B., Haining, W. N., Freeman, G. J., & Sharpe, A. H. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160801 · Cited by 848 · see citing works
Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression
Lin, H., Wei, S., Hurt, E. M., Green, M. D., Zhao, L., Vatan, L., Szeliga, W., Herbst, R., Harms, P. W., Fecher, L. A., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96113 · Cited by 580 · see citing works
Deconstructing repression: evolving models of co-repressor action
Perissi, V., Jepsen, K., Glass, C. K., & Rosenfeld, M. G. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2736 · Cited by 532 · see citing works
PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression
Tang, H., Liang, Y., Anders, R. A., Taube, J. M., Qiu, X., Mulgaonkar, A., Liu, X., Harrington, S. M., Guo, J., Xin, Y., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96061 · Cited by 520 · see citing works
Kiyasu, J., Miyoshi, H., Hirata, A., Arakawa, F., Ichikawa, A., Niino, D., Sugita, Y., Yufu, Y., Choi, I., Abe, Y., et al. (2015) · Blood · doi:10.1182/blood-2015-02-629600 · Cited by 469 · see citing works
PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas
Goodman, A. M., Patel, S. P., & Kurzrock, R. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.168 · Cited by 457 · see citing works
HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade
Woods, D. M., Sodré, A. L., Villagra, A., Sarnaik, A., Sotomayor, E. M., & Weber, J. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0077-t · Cited by 454 · see citing works
Lee, S. J., Jang, B., Lee, S.-W., Yang, Y., Suh, S., Park, Y.-M., Oh, S., Shin, J., Yao, S., Chen, L., et al. (2006) · FEBS Letters · doi:10.1016/j.febslet.2005.12.093 · Cited by 446 · see citing works
BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression
Zhu, H., Bengsch, F., Svoronos, N., Rutkowski, M. R., Bitler, B. G., Allegrezza, M. J., Yokoyama, Y., Kossenkov, A. V., Bradner, J. E., Conejo-Garcia, J. R., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.032 · Cited by 435 · see citing works
Li, H., Chiappinelli, K. B., Guzzetta, A. A., Easwaran, H., Yen, R.-W. C., Vatapalli, R. J., Topper, M. J., Luo, J., Connolly, R. M., Azad, N. S., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1782 · Cited by 428 · see citing works
Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need To Succeed
Gryder, B. E., Sodji, Q. H., & Oyelere, A. K. (2012) · Future Medicinal Chemistry · doi:10.4155/fmc.12.3 · Cited by 404 · see citing works
HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner
Malvaez, M., McQuown, S. C., Rogge, G. A., Astarabadi, M., Jacques, V., Carreiro, S. T., Rusche, J. R., & Wood, M. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213364110 · Cited by 400 · see citing works
Orillion, A., Hashimoto, A., Damayanti, N., Shen, L., Adelaiye-Ogala, R., Arisa, S., Chintala, S., Ordentlich, P., Kao, C., Elzey, B., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0741 · Cited by 373 · see citing works
Zheng, H., Zhao, W., Yan, C., Watson, C. C., Massengill, M. T., Xie, M., Massengill, C., Noyes, D. R., Martinez, G. V., Afzal, R., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2584 · Cited by 339 · see citing works
Hogg, S. J., Vervoort, S. J., Deswal, S., Ott, C. J., Li, J., Cluse, L. A., Beavis, P. A., Darcy, P. K., Martin, B. P., Spencer, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.011 · Cited by 308 · see citing works
Activation of MHC Class I, II, and CD40 Gene Expression by Histone Deacetylase Inhibitors
Magner, W. J., Kazim, A. L., Stewart, C., Romano, M. A., Catalano, G., Grande, C., Keiser, N., Santaniello, F., & Tomasi, T. B. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.12.7017 · Cited by 294 · see citing works
Mechanism of SMRT Corepressor Recruitment by the BCL6 BTB Domain
Ahmad, K. F., Melnick, A. M., Lax, S. A., Bouchard, D., Liu, J., Kiang, C. L., Mayer, S., Takahashi, S., Licht, J. D., & Privé, G. G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00454-4 · Cited by 282 · see citing works
Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer
Hughes, P. E., Caenepeel, S. R., & Wu, L. C. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.04.010 · Cited by 280 · see citing works
<i>CREBBP</i> Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
Jiang, Y., Ortega-Molina, A., Geng, H., Ying, H.-Y., Hatzi, K., Parsa, S., McNally, D., Wang, L., Doane, A. S., Agirre, X., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0975 · Cited by 278 · see citing works
Acetylation site specificities of lysine deacetylase inhibitors in human cells
Schölz, C., Weinert, B. T., Wagner, S., Beli, P., Miyake, Y., Qi, J., Jensen, L. J., Streicher, W. W., McCarthy, A. R., Westwood, N. J., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3130 · Cited by 271 · see citing works
Hatzi, K., Jiang, Y., Huang, C., Garrett-Bakelman, F. E., Gearhart, M. D., Γιαννοπούλου, Ε., Zumbo, P., Kirouac, K. N., Bhaskara, S., Polo, J. M., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.016 · Cited by 185 · see citing works
Self-citationAtsaves, V., Tsesmetzis, N., Chioureas, D., Kis, L. L., Leventaki, V., Drakos, E., Panaretakis, T., Grandér, D., Medeiros, L. J., Young, K. H., et al. (2017) · Leukemia · doi:10.1038/leu.2017.103 · Cited by 184 · see citing works
Briere, D. M., Sudhakar, N., Woods, D. M., Hallin, J. F., Engstrom, L. D., Aranda, R., Chiang, H., Sodré, A. L., Olson, P., Weber, J. S., et al. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2091-y · Cited by 146 · see citing works
Histone/protein deacetylases and T-cell immune responses
Akimova, T., Beier, U. H., Liu, Y., Wang, L., & Hancock, W. W. (2012) · Blood · doi:10.1182/blood-2011-10-292003 · Cited by 142 · see citing works
Huang, C., Hatzi, K., & Melnick, A. M. (2013) · Nature Immunology · doi:10.1038/ni.2543 · Cited by 139 · see citing works
Self-citationHistone deacetylases and epigenetic therapies of hematological malignancies
Mercurio, C., Minucci, S., & Pelicci, P. G. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.02.010 · Cited by 125 · see citing works
How do tumor cells respond to HDAC inhibition?
Newbold, A., Falkenberg, K. J., Prince, H. M., & Johnstone, R. W. (2016) · FEBS Journal · doi:10.1111/febs.13746 · Cited by 110 · see citing works
HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications
Harada, T., Ohguchi, H., Grondin, Y., Kikuchi, S., Sagawa, M., Tai, Y.-T., Mazitschek, R., Hideshima, T., & Anderson, K. C. (2017) · Leukemia · doi:10.1038/leu.2017.144 · Cited by 89 · see citing works
Cai, Y., Tsai, H.-C., Yen, R.-W. C., Zhang, Y. W., Kong, X., Wang, W., Xia, L., & Baylin, S. B. (2017) · Genome Research · doi:10.1101/gr.208108.116 · Cited by 88 · see citing works
Halsall, J. A., & Turner, B. M. (2016) · BioEssays · doi:10.1002/bies.201600070 · Cited by 85 · see citing works
Cycon, K. A., Mulvaney, K. M., Rimsza, L. M., Persky, D. O., & Murphy, S. P. (2013) · Immunology · doi:10.1111/imm.12136 · Cited by 83 · see citing works
Histone Deacetylase Inhibitors as Immunomodulators in Cancer Therapeutics
Shen, L., Orillion, A. R., & Пили, Р. (2016) · Epigenomics · doi:10.2217/epi.15.118 · Cited by 66 · see citing works
Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies
Matthews, G. M., Mehdipour, P., Cluse, L. A., Falkenberg, K. J., Wang, E., Roth, M., Santoro, F., Vidacs, E., Stanley, K. L., House, C. M., et al. (2015) · Blood · doi:10.1182/blood-2015-03-632984 · Cited by 60 · see citing works
Molecular and Biologic Analysis of Histone Deacetylase Inhibitors with Diverse Specificities
Newbold, A., Matthews, G. M., Bots, M. L., Cluse, L. A., Clarke, C. J. P., Banks, K.-M., Cullinane, C. M., Bolden, J. E., Christiansen, A. J., Dickins, R. A., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0626 · Cited by 46 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Regulation of PD-L1 expression in the tumor microenvironment
Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01027-5 · Cited by 681 · see citing works
Targeting the acetylation signaling pathway in cancer therapy
Dang, F., & Wei, W. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.001 · Cited by 109 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
- Authors
- Deng, S., Hu, Q., Zhang, H., Yang, F., Peng, C., & Huang, C.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Peng, Cheng
- Huang, Chuanxin
- Venue
- Molecular Cancer Therapeutics
- Published
- 2019-05-01
- Volume
- 18
- Issue
- 5
- Pages
- 900-908
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2920784460
- Cited by
- 116
- References
- 49
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 18 · 2023: 15 · 2022: 20 · 2021: 20 · 2020: 8 · 2019: 6
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31870872, 31800755)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- HDAC3, PD-L1 expression, B-cell lymphoma, HDAC3 inhibitors, PD-1/PD-L1 blockade, immunotherapy, epigenetic regulation, histone acetylation, BRD4, BCL6, SMRT, DNMT1, dendritic cells, tumor microenvironment, transcriptional repression
- MeSH terms
- Bromodomain Containing Proteins, Histone Deacetylase 3, Animals, Histone Deacetylases, Humans, Immunotherapy, Transcription Factors, Gene Expression Regulation, Neoplastic, Lymphoma, B-Cell, Cell Cycle Proteins, Epigenesis, Genetic, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-bcl-6, Histone Deacetylase Inhibitors, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
